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YAP mediates crosstalk between the Hippo and PI(3)K–TOR pathways by suppressing PTEN via miR-29

Nature Cell Biology volume 14, pages 1322–1329 (2012)Cite this article

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Abstract

Organ development is a complex process governed by the interplay of several signalling pathways that have critical functions in the regulation of cell growth and proliferation. Over the past years, the Hippo pathway has emerged as a key regulator of organ size. Perturbation of this pathway has been shown to play important roles in tumorigenesis. YAP, the main downstream target of the mammalian Hippo pathway, promotes organ growth, yet the underlying molecular mechanism of this regulation remains unclear. Here we provide evidence that YAP activates the mammalian target of rapamycin (mTOR), a major regulator of cell growth. We have identified the tumour suppressor PTEN, an upstream negative regulator of mTOR, as a critical mediator of YAP in mTOR regulation. We demonstrate that YAP downregulates PTEN by inducing miR-29 to inhibit PTEN translation. Last, we show that PI(3)K–mTOR is a pathway modulated by YAP to regulate cell size, tissue growth and hyperplasia. Our studies reveal a functional link between Hippo and PI(3)K–mTOR, providing a molecular basis for the coordination of these two pathways in organ size regulation.

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Figure 1: YAP regulates mTOR activity.
Figure 2: PTEN is a critical mediator of YAP in the regulation of mTORC1/2 activity.
Figure 3: YAP directly induces the expression of miR-29c to target PTEN.
Figure 4: YAP regulates cell size and tissue growth through modulation of PI(3)K and mTOR.

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Acknowledgements

We thank F. Furnari and M. Wicha for reagents. We thank J. Zhao for technical help, and J. Kim and B. Zhao for thoughtful discussions. The deep-sequencing service was provided by LC Sciences. K.T. was supported in part by the UCSD Graduate Training Program in Cellular and Molecular Pharmacology. K-L.G. is supported by grants from the NIH.

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Authors and Affiliations

  1. Department of Pharmacology and Moores Cancer Center, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA

    Karen Tumaneng, Ryan C. Russell & Kun-Liang Guan

  2. Biomedical Sciences Graduate Program, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA

    Karen Tumaneng, Harihar Basnet & Navin Mahadevan

  3. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    Karin Schlegelmilch, Dean Yimlamai & Fernando D. Camargo

  4. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA

    Julien Fitamant & Nabeel Bardeesy

  5. Institute for Chemistry/Biochemistry, FU Berlin, Berlin 14195, Germany

    Karin Schlegelmilch

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Contributions

K.T. performed the experiments. K.S. conducted the LY294002 animal experiment. K.T. and R.C.R. performed fluorescent immunohistochemistry staining experiments. D.Y. prepared mouse tissue slides for immunohistochemistry experiments. K.T. and H.B. performed luciferase and ChIP assays. K.T. and N.M. conducted flow cytometry experiments. J.F. and N.B. provided the Mst1/2-knockout mouse liver tissues. K.S. and F.D.C. designed the LY294002 animal experiment. K.T. and K-L.G. designed experiments and wrote the manuscript.

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Correspondence to Kun-Liang Guan.

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Tumaneng, K., Schlegelmilch, K., Russell, R. et al. YAP mediates crosstalk between the Hippo and PI(3)K–TOR pathways by suppressing PTEN via miR-29. Nat Cell Biol 14, 1322–1329 (2012). https://doi.org/10.1038/ncb2615

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